Abstract
Background and Purpose : Transient hypofunction of NMDARs
represents a convergence point for the onset and further development of
psychiatric disorders, including schizophrenia. Although the cumulative
evidence indicates dysregulation of the hippocampal formation in
schizophrenia, the integrity of the synaptic transmission and plasticity
conveyed by the somatosensorial inputs to the dentate gyrus, the
perforant path synapses, have barely been explored in this pathological
condition.
Experimental Approach : We identified a series of synaptic
alterations of the lateral and medial perforant paths, in animals
neonatally treated with the NMDAR antagonist MK-801. The dysregulation
here reported suggests decreased cognitive performance, for which the
dentate gyrus is critical.
Key Results : We identified alterations in the synaptic properties
of the lateral and medial perforant paths to the dentate gyrus synapses
in MK-801-treated animals. Altered glutamate release and decreased
synaptic strength precede an impairment in the induction and expression
of LTP and cannabinoid 1 receptor (CB1R)-mediated LTD.
Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol, the
endogenous ligand of the CB1R, we restored the LTD in
animals treated with MK-801. Additionally, we show for the first time
that spatial discrimination, a cognitive task that requires dentate
gyrus integrity, is impaired in animals exposed to transient
hypofunction of NMDARs.
Conclusion and Implications : Descriptive and mechanistic evidence
showing the dysregulation of glutamatergic transmission and synaptic
plasticity from the entorhinal cortex to the dentate gyrus is presented.
These findings may explain the cellular dysregulations underlying the
altered cognitive processing in the dentate gyrus associated with
schizophrenia.